MinireviewNitric oxide and cardiac function
Introduction
When the endothelial derived relaxing factor was identified as nitric oxide (NO), vasodilatation was believed to be the only activity of the compound, while its release was attributed to the vascular endothelial cells only. Later on, it was discovered that NO affects the function of various organs, including myocardium, and is produced by several cell types, including cardiomyocytes. The effect of NO on the vasculature has also been seen to include protection of the vessel wall (and the heart) against the no-reflow phenomenon which follows a period of ischemia. A chronic vascular effect of NO is the prevention of the formation of atherosclerotic plaques (Penna et al., 2003).
It has been observed that in addition to the synthesis mediated by NO-synthase (NOS), also a non-enzymatic mechanism can lead to the production of NO. At present it is known that NO takes part in the regulation of myocardial contractility and contributes to myocardial protection in ischemic pre- and postconditioning. Successful studies have also been devoted to its role in heart failure and in the limitation of left ventricular remodeling (Dawson et al., 2005, Godecke et al., 2001). Thus in the present review we consider the role of NO in the regulation of contractility and rate in normal and failing hearts and in myocardial protection as well as its effect in limiting ventricular remodeling.
The most studied effect induced by increased endothelial release of NO or by NO donors is vasodilatation. This effect concerns both systemic and pulmonary vascular beds. It is worth noting that inhaled NO is increasingly being used to treat pulmonary hypertension particularly in newborns (Ostrea et al., 2006).
In spite of the well known vasodilator effect induced by increased endothelial release of NO or by NO donors, very low concentrations of NO have been seen to induce vasoconstriction (Graser and Vanhoutte, 1991, Pearson and Vanhoutte, 1993).
Graser and Vanhoutte (1991) showed that hypoxic constriction of canine coronary arteries with intact endothelium can be reverted into relaxation by the NOS inhibitor NG-nitro-l-arginine (L-NNA). Such an observation suggests a role of nitric oxide in vasoconstriction. In the same article the authors report that, if hypoxic constriction is absent in vessels without endothelium, it appears after treatment with small doses of cGMP and of the NO donor 3-morpholinosydnonimine (SIN-1).
While the NO-induced vasodilatation is the consequence of a reduction of intracellular Ca2+ concentration, brought about by a guanylyl cyclase (GC)–protein kinase G (PKG) pathway, the vasoconstriction is likely to be due to an increase of this concentration (Kojda and Kottenberg, 1999).
With no doubt the fundamental signaling role of NO in cellular function is the activation of GC which leads to the formation of cGMP, which in turn, leads to PKG activation. This signaling pathway is of fundamental importance for vascular relaxation. In fact, NO and cGMP activate PKG and inhibit phosphoinositide hydrolysis and intracellular calcium mobilization. PKG also activates myosin phosphatase, further promoting vascular relaxation. Yet, the NO–cGMP–PKG pathway counteracts the cellular activation stimulated by vasoconstrictors acting on Gq-coupled receptors (e.g. angiotensin II, endothelin and vasopressin receptors) (Tang et al., 2003 and references therein).
It is noteworthy that intracellular cGMP can be produced by two GC types: cytosolic (soluble: sGC) and membrane bound (particulate: pGC), which are stimulated by NO and natriuretic peptides, respectively. Depending on sub-cellular localization and regulation of these enzymes, cGMP produced by either pGC or sGC exerts different complementary effects in physiological and pathological conditions (Cerra and Pellegrino, 2007).
Another important signaling mechanism for NO is the possibility to be transferred to cysteine sulphydryls in a protein-thiol S-nitrosylation (Broillet, 1999). Importantly, protein S-nitrosylation may lead to the activation of various proteins involved in excitation–contraction coupling, including the L-type Ca2+ channel and the Ry/R (Hare, 2003 and references therein).
In addition to the vasomotor tone, data support a role for NO effects on myocardial function via cGMP and S-nitrosylation mechanisms (Saraiva and Hare, 2006). Therefore, the scope of the present review is to summarize the complex and diverse involvement of NO in the regulation of cardiac function.
Section snippets
Nitric oxide and myocardial contractility
The activity of vascular NO can affect myocardial contraction both because coronary capillary endothelial cells are close to cardiomyocytes and an increase in flow can elicit the Gregg's phenomenon (Brady et al., 1993, Brutsaert et al., 1998, Brutsaert, 2003). Myocardial contractility is also affected by cardiomyocyte-released NO.
Nitric oxide and heart rate
Usually endogenous NO has a positive chronotropic effect. In fact, Pagliaro et al. (1996) showed in the anesthetized dog that NOS inhibition with L-NNA induces a reduction in heart rate even if the vagi are sectioned and any increase in pressure is prevented by connecting the two femoral arteries with a blood reservoir (Pagliaro et al., 1996). Moreover, Ward and Angus (1993) reported that in the rabbit, NOS inhibition induces bradycardia in spite of pharmacological blockade of the autonomic
Nitric oxide in heart failure
In dogs with pacing-induced cardiac failure, Traverse et al. (2002) observed a reduction in O2 consumption and, consequently, in coronary flow, suggesting a down-regulation of energy metabolism. In these animals, NOS inhibition by L-NNA increased both oxygen consumption and coronary flow, indicating that in the failing heart NO can exert a tonic inhibition on cell respiration. It was also seen that in dogs with heart failure, selective iNOS inhibition with S-methyl-isothiourea increases left
Nitric oxide and myocardial protection
Myocardial protection is the limitation of the ischemia–reperfusion (I/R) injury induced by ischemic pre- and postconditioning. Ischemic preconditioning (IP) can be obtained with one or more brief (e.g. 2–5 min) coronary occlusions performed before period of ischemia that is sufficiently long (e.g. 30 min) to cause myocardial cell death. Ischemic postconditioning (Post-C) can be obtained when one or more brief (e.g. 10–90 s) interruptions of coronary flow are performed at the beginning of
Nitric oxide and heart remodeling
After myocardial infarction (MI) the left ventricle shows hypertrophy of cardiomyocytes, interstitial fibrosis, dilatation and changes in shape. All these alterations form the so-called remodeling which is responsible for a progressive adaptation (compensation) followed by deterioration of contractile function, ultimately leading to heart failure. Remodeling is also associated with increased vascular capacity of the healthy myocardium and angiogenesis in the injured part during healing (Kalkman
Conclusions
In recent years, major advances have been made toward understanding the role of NO in the biology of the heart. Increased NO availability is a common feature of diverse, apparently unrelated, biological actions on the heart. NO plays a crucial role in the cardioprotection against I/R injury, in the regulation of cardiac contractility in normal and failing heart, and in the post-infarct remodeling.
NO is involved in the regulation of myocardial contractility, which is enhanced by low
Acknowledgements
The authors wish to thank the “Compagnia di San Paolo”, Torino, the National Institute for Cardiovascular Research, Bologna, and the Italian Ministry of University and Research (MIUR), Rome for the financial contribution to their investigation included in the present review.
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2022, Current Research in PhysiologyCitation Excerpt :As a result, myocardial contractility increases. At concentrations, NO causes to produce more amounts of cGMP, by which cardiodepression occurs in response to protein kinase G (PKG) activation with blockade of sarcolemma Ca2+ channels (Rastaldo et al., 2007; Wang et al., 2021). In our study, using L-arginine resulted in increasing NO level so that it exerted a destructive effect and increased arrhythmia in the ketamine/xylazine group.